We will establish a center that combines functional genomic and computational research to model a prototype signal transduction pathway. Work at the center will focus on the "Alpha Project." The overall goal of the work is to gain the ability to predict the behavior of a well-studied biological regulatory system at the level of individual cells. The system is the G-protein receptor coupled signal transduction pathway that governs the response of haploid MATa S. cerevisiae to the mating pheromone, a factor. This pathway is a prototype for regulatory networks that govern response to external stimuli in higher eukaryotes. It is also sufficiently tractable to facilitate development of the numerous functional genomic experimental and computational methods that we hope to bring into being here; and sufficiently paradigmatic so that successful experimental and computational tactics can be ported rapidly to other systems in other organisms. During the project period, we will: 1) Develop experimental means to measure system output and key intermediate quantities from single cells and populations of cells. 2) Develop computational means to simulate the behavior of cells and populations of cells. 3) Use these methods to build models that predict the quantitative behavior of cells over time and in response to defined perturbations. 4) Accomplish heuristic goals including learning to perform combined experimental work and learning to develop investigators in a multidisciplinary genomic research environment. Work at the Center will also deepen our understanding of important but so-far-poorly understood scientific questions, including the extent and importance of epigenetic variation, and the means by which dynamic and quantitative aspects of biological system behavior are controlled. The Center will develop functional genomic and computational methods that are scalable to systematic large-scale data collection and that are applicable to similar studies of other organisms, including humans. The Center will attract and train in genomic research numbers of researchers, many of whose backgrounds are in physics, mathematics, and other nonbiomedical disciplines, who will continue to work at this disciplinary interface. The center may thus serve as a prototype for subsequent combined experimental and computational laboratories that strive to understand genome function.